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How the battle lines over CRISPR were drawn

The U.S. Patent Trial and Appeal Board ruled today in favor of the Broad Institute in the high stakes battle over who will control the valuable intellectual property linked to CRISPR, the powerful genome-editing tool. The ruling came after the feature below, from the 16 February issue of Science, was prepared. The decision may be appealed by the University of California, however, and many other CRISPR-related patent applications have been filed by the companies and scientists trying to commercialize its discovery, so the business battle will no doubt continue.

CRISPR battle update

In early 2012, Emmanuelle Charpentier, a little-known French microbiologist who would soon meet worldwide fame, contacted her old friend Rodger Novak to tell him about her recent studies at Umeå University in Sweden of the mechanisms behind a novel bacterial immune system. "She said, ‘Hey, what do you think about CRISPR?’" recalls Novak, a biotech executive who more than a decade earlier had worked with Charpentier in academic labs studying antibiotic resistance. "I had no clue what she was talking about."

It was only later that Novak learned that Charpentier, in collaboration with a prominent structural biologist, Jennifer Doudna of the University of California (UC), Berkeley, had transformed the CRISPR immune system into a tool that could edit genomes with great ease. As they and colleagues noted in what has become a landmark Science paper, published online 28 June 2012, this tool had "considerable potential."

That November, Novak, who by then had become a vice president at Sanofi in Paris, and another old friend, Shaun Foy, a venture capitalist in Vancouver, Canada, discussed CRISPR's commercial potential during a surfing trip to the challenging, frigid waters off the northern tip of Vancouver Island. Neither had ever surfed, but they both liked adventures. So Foy's assessment, which came a month later after he had done what he calls his "diligencing," wasn't surprising. "He said I had to leave my job," Novak says.

[The patent fight] reminds me of reading about really unhappy rich people. They have such a big blank check that they just make each other miserable.

George Church, Harvard University

Novak, Foy, and Charpentier began speaking with others at the CRISPR research front about starting a company. "We were, as far as I know, the first ones to really think of that and really try to put something together," says Charpentier, who is now at the Max Planck Institute for Infection Biology in Berlin. They set out to bring all the leading lights of CRISPR on board. It was a tiny research community then—in 2012 only 126 papers were published on CRISPR, compared with 2155 last year—and this simple vision seemed healthy for the field: practical and intellectually turbocharged. "We thought in the beginning it would be very important to bring everyone together," Charpentier says.

After discussing the idea with Doudna, they floated the concept by two key CRISPR researchers in Cambridge, Massachusetts: George Church at Harvard University and his former postdoc Feng Zhang of the Broad Institute, who had just published their own widely noticed Science papers showing that the CRISPR system could guide its bacterial enzyme, Cas9, to precisely target and cut DNA in human cells. "One of the goals was to simplify the process of intellectual property," Charpentier says.

But the attempt at unity collapsed—with a good deal of noise and dust. "I wish that it had worked out differently," says Doudna, who also liked the concept of everyone working together. Over the next year and a half, as the science grew even more compelling and venture capital (VC) beckoned, the jockeying to start CRISPR companies became intense. The small community of researchers was rent apart by concerns about intellectual property, academic credit, Nobel Prize dreams, geography, media coverage, egos, personal profit, and loyalty. Adding to the divisive forces were the interests of the prestigious and powerful institutions that had a stake in the spoils—which in addition to UC, Broad, and Harvard included the Massachusetts Institute of Technology in Cambridge and the University of Vienna.

In the end, three companies formed to try to exploit CRISPR to create novel medicines, while Broad and two other companies licensed the technology to partners that hoped to engineer everything from improved crops and livestock to better animal models and industrial chemicals. A billion dollars poured into what might be called CRISPR Inc. from VC firms, pharmaceutical companies, and public stock offerings. Tens of millions of that money went to lawyers as the companies and the academic license holders faced each other down in a battle royale at the U.S. Patent and Trademark Office (USPTO). "It reminds me of reading about really unhappy rich people," says Church of the epic patent fight. "They have such a big blank check that they just make each other miserable."

As the players anxiously await a ruling from USPTO, Science took a close look at how the enterprise fractured, drawing on documents from the patent litigation, Securities and Exchange Commission filings, licensing agreements, and interviews with the central figures. Church, who describes himself as "an inclusive guy" and made his own attempt to bring the top researchers together under one roof, believes that in the long run the splintering of the field will probably work out fine for the companies, their investors, the principal researchers, and the public. "It's good enough," says Church, who has equity in two CRISPR companies that focus on human therapeutics. "But it's not all for the good."

Dividing the pie

Two institutions and researcher Emmanuelle Charpentier claim CRISPR intellectual property. They have given birth to companies that have licensed the technology for multiple—and in many cases overlapping—applications in human therapeutics, agriculture, and industry. Scientists hold major stakes in several companies (see table below). Hover over a researcher, a licensee or an application to see its connections.

Human therapeutics:

Intellia

CRISPR Therapeutics

Editas Medicine

Nonhuman therapeutics:

Caribou Biosciences

ERS Genomics

Broad Institute

Dividing the pie

Two institutions and researcher Emmanuelle Charpentier claim CRISPR intellectual property. They have given birth to companies that have licensed the technology for multiple—and in many cases overlapping—applications in human therapeutics, agriculture, and industry. Scientists hold major stakes in several companies (see table below).

(Interactive)J. You/Science; (Graphic)G. Grullón/Science

CRISPR first became a business with yogurt.

The dairy industry uses the bacterium Streptococcus thermophilus to convert lactose into lactic acid, which gels milk. Viruses called bacteriophages can attack S. thermophilus, spoiling the yogurt culture. In 2007, Rodolphe Barrangou and Philippe Horvath were working at Danisco, one of the world's leading makers of yogurt cultures, when they found that the S. thermophilus genome contains odd chunks of repeated DNA sequences—so-called clustered regularly interspaced short palindromic repeats (CRISPR), which Spain's Francisco Mojica had first described in 1993 in the genome of the salt-loving microbe Haloferax mediterranei. The Danisco team found that the CRISPR sequences match the phage DNA, enabling S. thermophilus to recognize and fight off infections.

DuPont, which acquired Danisco in 2011, began using the insights to create bacteriophage-resistant S. thermophilus for yogurt and cheese production. Today, "whether you've had yogurt in Tel Aviv or nachos in California, you've eaten a CRISPR-enhanced dairy product," says Barrangou, who is now a food scientist at North Carolina State University in Raleigh.

Yet the idea that CRISPR could serve as a general-purpose genome-editing tool did not surface until a 19 December 2008 Science paper by Erik Sontheimer and Luciano Marraffini at Northwestern University in Evanston, Illinois. Sontheimer and his postdoc Marraffini were the first to show just how CRISPR protected bacteria: by identifying and crippling invaders' DNA. "From a practical standpoint, the ability to direct the specific, addressable destruction of DNA … could have considerable functional utility, especially if the system can function outside of its native bacterial or archaeal context," they wrote.

USPTO, however, rejected their patent application. "The vision and idea were out there, but we hadn't reduced it to practice," says Sontheimer, who is now at the University of Massachusetts Medical School in Worcester. "When we filed our patent in 2008 there were a million mechanistic questions."

In 2011, Doudna co-started Caribou Biosciences as what she calls "a research tool company" to exploit the possibility that CRISPR could be used to simplify detection of viral infections like HIV. But the real flowering of CRISPR Inc. didn't begin until the next 2 years, when this obscure bacterial immune system showed its power as the versatile tool that Sontheimer and Marraffin had only imagined. First came Doudna and Charpentier's paper describing a CRISPRCas9 system that could cut DNA in a test tube. Six months later, in January 2013, Zhang (working with Marraffini), Church, Doudna, and a fourth group separately reported that they could export CRISPR-Cas9 to human cells, which meant that it might be put to work in medical treatments.

That was when Charpentier made the rounds, talking to one CRISPR expert after another about commercializing the technology far beyond the research tools Caribou was pursuing. Among those she approached was Zhang. "It would have been really great to work with Emmanuelle," he says.

But geography intervened. Her team had a plan to be headquartered in Switzerland and was backed by a California-based VC firm, Zhang notes. He, on the other hand, "had the opportunity to build a really strong team in Boston," he says. Boston-based investors were interested, and Eric Lander, Broad's president, served as a consultant for one of them. Lander declined requests to comment for this article, noting through a spokesperson that he had "no business relationships with any of the CRISPR companies." But Lander acknowledged that he "did meet with VCs to actively stimulate interest in forming companies to license the technology in ways that could maximize patient benefit."

It's been an incredible fight over credit. Everyone is trying to jockey themselves and minimize what others did.

Erik Sontheimer, University of Massachusetts Medical School

The nascent partnership between Doudna and Charpentier's group also became strained, but both of them declined to discuss the details. "It's delicate," Charpentier says. Says Doudna: "She made various decisions about really going her own way with respect to her commercial involvement that I completely respect."

At this point, investors weren't tripping over themselves. "When we said ‘CRISPR,’ people were a bit confused," Charpentier recalls. "There's a lot of food associated with ‘crisper.’ You have crispy salad in Sweden. In the U.S., there are Krispy Kreme doughnuts."

Church says the field only drew serious investment, spawning new companies and new rivalries, after a team led by Harvard's Chad Cowan and Kiran Musunuru showed in the 4 April 2013 issue of Cell Stem Cell that CRISPR was far superior to existing genomeediting tools. Scientists had harnessed and commercialized other enzymes for genome editing, notably ones that relied on so-called zinc fingers and others known by the acronym TALENs (transcription activator-like effector nucleases). In the Cell Stem Cell paper, the researchers did a head-to-head comparison of CRISPR and TALENs. CRISPR, they found, was far more efficient at creating the targeted mutations. "Up until that point, CRISPR was just another scissors," says Church, but now the new technique stood out.

Cowan and Musunuru teamed up with Church and Harvard's Derrick Rossi, who had recently co-founded a biotech, Moderna Therapeutics, that had broken records for investments. They started to explore forming a CRISPR company. "We talked to all the VCs in the space," says Musunuru, now a cardiologist at the University of Pennsylvania. Along the way, they learned that Charpentier's team and Zhang and his colleagues at Broad were also doing the VC dog-and-pony show. "It was clear that people had competing interests, even though the real issues didn't come out to public display until later," Musunuru says.

Some scientists went their own way to make sure that they, and not the investors, would shape the companies, whereas others hoped to make more money by affiliating with this or that VC firm. "They were thinking the next Genentech—hundreds of millions of dollars," says Cowan of some of the earlier players who decided against launching a company with him. And there were bruised relationships. "It's been an incredible fight over credit," Sontheimer says. "Everyone is trying to jockey themselves and minimize what others did."

By the end of 2013, Charpentier, Novak, Foy, and Cowan had joined forces in CRISPR Therapeutics. Zhang, Church, and Doudna helped co-found Editas Medicine, which was born out of Broad. Sontheimer, Marraffini (now at The Rockefeller University in New York City), Rossi, and Barrangou are all co-founders of Intellia Therapeutics. Other pharmaceutical and biotechnology companies soon jumped in, paying steep licensing and collaboration fees to the CRISPR startups, as well as to Broad.

These companies stress that they have distinct development "pipelines" and business strategies. But there's a great deal of overlap: For example, CRISPR Therapeutics and Editas have both made sickle cell disease and Duchenne muscular dystrophy a priority, and Intellia and Editas both have programs targeting the liver disease α-1 antitrypsin deficiency and collaborations that focus on engineering T cells to fight cancer. "At the 10,000-foot level they're all similar," Doudna says. Yet she is unconcerned about duplication. "There's plenty of space in the gene-editing world for multiple entities." Charpentier notes that some redundancy is a good thing to solve tough biomedical problems. "How many pharmaceutical industries and biotechs are working on the same thing?" she asks.

*As of 9 February 2017

(Table data) SEC S-1 Filings

The developing patent battle has led to further rifts. Doudna, Charpentier, and collaborators—who collectively are represented by UC—first filed a patent application in May 2012, whereas the Broad group did not file a patent claim until that December. But Broad, which soon filed 11 more patents to support its central claim that Zhang's team had invented the first CRISPR system to edit human cells, paid USPTO to fast-track the review of its applications. To the surprise of many in the field, USPTO began issuing CRISPR patents to Broad in April 2014 before deciding on the UC Regents' earlier patent application.

Church says he had serious misgivings about Broad's patent position and the legal wrangling, which Editas bankrolled. "I almost quit," Church says. Broad's first patent application was rejected, he says, and Broad's response to USPTO—in particular, a declaration from Zhang—"was quite unfriendly and it questioned Jennifer's veracity and authenticity." The declaration noted that Doudna acknowledged Church's help in her January 2013 publication about making CRISPR work in human cells. "I just thought she was being nice, and holding that against her like she got vital information from me is odd." (Broad, Editas, and the other parties in the patent dispute refused to discuss the details.)

Doudna left Editas a few weeks after the patent was granted. She says she had family commitments at home in Berkeley and was tired of traveling to Cambridge but adds, "You're welcome to draw your own conclusions." A year later, she became a "cofounder" of Intellia—based in Cambridge. And at UC's behest, USPTO declared a patent "interference" on 11 January 2016, which triggered an expensive, contentious fight that the companies are financing.

The track record of earlier gene-editing approaches suggests that the CRISPR companies pursuing medical therapies have a long road ahead. In 2009, for example, Sangamo Therapeutics in Richmond, California, began using zinc finger nucleases to modify genes in immune cells from HIV-infected people, hoping to make the cells resistant to the virus. Yet the company still doesn't have an approved therapy. Similarly, cancer immunotherapies designed with TALENs by Cellectis, headquartered in Paris, have been tested in people since 2015, but they've only been given to two patients so far.

There's no reason to think CRISPR would succeed any faster in applications like those, says Dana Carroll at the University of Utah in Salt Lake City, who did pioneering work to develop the zinc finger technology. "If you have just one target you're going to hit over and over again and it's part of a big project, it doesn't matter which platform you use," Carroll says. "CRISPR's a great advantage only when you're feeling your way, like you do in a research project."

Nor is it clear that CRISPR will offer an easier path to genetically modified crops and livestock than other genetic engineering techniques do. That will depend on whether government regulators exempt CRISPR-modified organisms, which are made without transfering DNA from one species to another, from the scrutiny that genetically modified organisms now get.

USPTO's appeal board is expected to announce its decision in the next few weeks. Sherkow and Contreras predict each party will likely wind up with some patent rights and will ultimately cross license. But the decision is sure to shake up the industry, Doudna says. "It does raise this dilemma of what happens in the future with all of these various partnerships that have been put in place," she says. "They will have to be re-evaluated."

In spite of the uncertainties, Barrangou, who notes that for a decade he was one of only a handful of researchers working on CRISPR, says people still underestimate how large CRISPR Inc. will become. "We're not even getting started," he says. "People say, ‘I can't wait for the bubble to burst.’ Talk to them 6 months later and they say, ‘I can't believe this.’ Talk to them 5 years later and they'll still say they can't believe it."